Process for the preparation of 3-substituted 5-amino-6H-thiazolo[4,5-d]pyrimidine-2,7-dione compounds

Abstract

The present invention relates to a process for synthesizing a compound of formula (I), R1 is H or C1-6alkyl; R2 is H or hydroxy; or pharmaceutically acceptable salt or diastereomer thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.

The invention claimed is: 
     
       1. A process for the preparation of a compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H or C 1-6 alkyl; and 
 R 2  is H or hydroxy; 
 or a pharmaceutically acceptable salt, or an enantiomer or diastereomer thereof; 
 
         the process comprising one or more of the following steps: 
         a) forming a compound (III) from a compound of formula (II); 
       
       
         
           
           
               
               
           
         
         b) forming a compound (IV) from compound (III); 
       
       
         
           
           
               
               
           
         
         c) forming a compound (V) from compound (IV); 
       
       
         
           
           
               
               
           
         
         d) forming a compound (VI) from compound (V); 
       
       
         
           
           
               
               
           
         
         e) forming a compound (VII) from compound (VI); 
       
       
         
           
           
               
               
           
         
         f) forming a compound (VIII) from compound (VII); 
       
       
         
           
           
               
               
           
         
         g) forming a compound (IX) from compound (VIII); 
       
       
         
           
           
               
               
           
         
         h) forming a compound of formula (X) from compound (IX); 
       
       
         
           
           
               
               
           
         
         wherein R 1  is H or C 1-6 alkyl; 
         i) forming a compound of formula (XII) by reacting compound (X) with a compound of formula (XI); 
       
       
         
           
           
               
               
           
         
         wherein R 2  is H or hydroxy; 
         j) forming a compound of formula (I) via the hydrolysis of the compound of formula (XII), 
       
       
         
           
           
               
               
           
         
         k) forming a compound of formula (XV) from the compound of formula (I); 
       
       
         
           
           
               
               
           
         
         wherein Acid is selected from D-glutamic acid, L-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-amino-benzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(−)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid; and step l) forming a compound of formula (I) via dissociation from the compound of formula (XV). 
       
     
     
       2. The process according to  claim 1  consisting of step a) to step l). 
     
     
       3. The process according to  claim 1 , wherein R 1  is methyl. 
     
     
       4. The process according to  claim 1  for the synthesis of the compound of formula (XV), 
       
         
           
           
               
               
           
         
         wherein: 
         Acid is selected from D-glutamic acid, L-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(−)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid and lactobionic acid; 
         R 1  is H or C 1-6 alkyl; and 
         R 2  is H or hydroxy; 
         or a pharmaceutically acceptable enantiomer or diastereomer thereof. 
       
     
     
       5. The process according to  claim 4  for the synthesis of compound (XVa), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, or an enantiomer or diastereomer thereof. 
       
     
     
       6. The process according to  claim 1 , characterized in that the formation of the compound (VI) in step d) is performed in the presence of a base with an acylating reagent and a catalyst, wherein the catalyst is selected from DMAP, MgCl 2  and Bu 2 SnO. 
     
     
       7. The process according to  claim 6 , wherein the amount of catalyst is 0.001-0.2 eq. 
     
     
       8. The process according to  claim 1 , characterized in that the formation of the compound of formula (X) in step h) is performed in the presence of an acylating reagent with an acid in a solvent, wherein the solvent is selected from DCM, CHCl 3 , 2-MeTHF, toluene, IPAc and EtOAc. 
     
     
       9. The process according to  claim 1 , characterized in that the formation of the compound of formula (XV) in step k) is performed in the presence of an acid in an organic solvent, wherein the acid is selected from: D-glutamic acid, L-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(−)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid. 
     
     
       10. The process according to  claim 9 , wherein the organic solvent is selected from: MeOH, EtOH, n-propanol, IPA, MeCN, acetone, THE, and toluene. 
     
     
       11. The process according to  claim 10 , wherein the solvent is added with an additive, wherein the additive is water. 
     
     
       12. The process according to  claim 11 , wherein the volume ratio of water to solvent (V water /V solvent ) is 0.005-0.015. 
     
     
       13. The process according to  claim 11 , wherein the solvent is MeCN, and wherein the volume ratio of water to MeCN (V water /V MeCN ) is 0.005. 
     
     
       14. The process according  claim 1 , characterized in that the formation of compound of formula (I) via dissociation from compound of formula (XV) in step l) is performed in the presence of a base in a solvent, followed by a recrystallization procedure using a further solvent; wherein the solvent used in the recrystallization procedure is a mixture of water and an organic solvent selected from: MeOH, EtOH, and n-propanol. 
     
     
       15. The process according to  claim 14 , wherein the weight percentage of organic solvent in water is 0-30 wt. %. 
     
     
       16. The process according  claim 1 , characterized in that the formation of compound of formula (I) via dissociation from the compound of formula (XV) in step l) is performed in the presence of a base in a solvent, followed by a recrystallization procedure using a further solvent;
 wherein the solvent used in recrystallization procedure is a mixture of a polar organic solvent and a non-polar organic solvent; 
 wherein the polar organic solvent is selected from MeOH, EtOH, n-propanol and n-butanol; 
 and wherein the non-polar organic solvent is selected from n-heptane and n-hexane. 
 
     
     
       17. The process according to  claim 16 , wherein the weight percentage of polar solvent in the solvent mixture is 0-80 wt. %. 
     
     
       18. A compound of formula (XV), 
       
         
           
           
               
               
           
         
         wherein: 
         Acid is selected from D-glutamic acid, L-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(−)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid; 
         R 1  is H or C 1-6 alkyl; and 
         R 2  is H or hydroxy; 
         or a pharmaceutically acceptable salt, or an enantiomer or diastereomer thereof. 
       
     
     
       19. A compound of formula [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate citric acid. 
     
     
       20. The process of  claim 4 , wherein Acid is selected from the group consisting of: 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, and 2,5-dihydroxybenzoic acid. 
     
     
       21. The process of  claim 4 , wherein Acid is citric acid. 
     
     
       22. The process of  claim 6 , wherein the amount of catalyst is 0.05 eq. 
     
     
       23. The process of  claim 6 , wherein the catalyst is Bu 2 SnO. 
     
     
       24. The process of  claim 8 , wherein the solvent is EtOAc. 
     
     
       25. The process of  claim 8 , wherein the acid is selected from the group consisting of: 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, and 2,5-dihydroxybenzoic acid. 
     
     
       26. The process of  claim 8 , wherein the acid is citric acid. 
     
     
       27. The process of  claim 10 , wherein the organic solvent is MeCN. 
     
     
       28. The process of  claim 14 , wherein the volume ratio of water to organic solvent (V water V solvent ) is 0.005. 
     
     
       29. The process of  claim 15 , wherein the weight percentage of organic solvent in water is 7.8 wt. %. 
     
     
       30. The process of  claim 14 , wherein the organic solvent is EtOH. 
     
     
       31. The process of  claim 16 , wherein the solvent used in the recrystallization procedure is a mixture of n-propanol and n-heptane. 
     
     
       32. The process of  claim 17 , wherein the weight percentage of polar solvent in the solvent mixture is 60-75 wt. %. 
     
     
       33. The process of  claim 17 , wherein the weight percentage of polar solvent in the solvent mixture is 60 wt. %. 
     
     
       34. The compound of  claim 18 , wherein Acid is selected from 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, and 2,5-dihydroxybenzoic acid. 
     
     
       35. The compound of  claim 18 , wherein Acid is citric acid.